It is well known that certain therapeutically active agents are not suitable for oral administration for various reasons associated, inter alia, with either a high level of metabolism in the liver (“first pass effect”) or a high level of gastrointestinal degradation. Transdermal or transmucosal formulations have been developed in order to circumvent these drawbacks. Specifically, pharmaceutical compositions for transdermal or transmucosal administration have several advantages over oral forms, including elimination of the problems associated with metabolism of the therapeutically active agent by the liver and with gastric degradation of the active agent. However, transdermal and transmucosal compositions face problems associated with the kinetics of passage of the therapeutically active agents from the surface of the skin into the bloodstream.
Indeed, the skin is a heterogeneous tissue which comprises two layers: the dermis and the outer most epidermis layer, which can be further divided into the stratum corneum and the viable epidermis. These layers provide the skin with barrier capacities against the entry of foreign substances such as drugs. The stratum corneum acts as a physical diffusive barrier, whereas the epidermis and dermis can provide in addition a biochemical or enzymatic barrier.
Studies concerning the absorption of therapeutically active agents by the skin have focused for the most part on improving the rate of absorption of the active agents ingredients through the skin, rather than paying any attention to the fate of the absorbed active agents. For example, the use of permeation enhancers was proposed in order to increase the initial rate of penetrated active agents through the skin. The term “permeation enhancer” generally refers to any molecule that promotes the reversible diffusion of an active agent through the skin or mucous membranes, and any solubilizing agent that promotes the partitioning of the active agent between the vehicle and the horny layer of the epidermis or of the mucous membranes. Most enhancers affect the stratum corneum barrier capacities, i.e., they reversibly alter the stratum corneum structure, thus increasing drug diffusivity and solubility. This indeed enhances skin penetration of the active agents, but this may also result in the direct absorption of a large amount of the drug through the tissues, leading to a peak active agent concentration in the blood in the immediate hours following the application of the composition. This initial peak is often followed by a trough in blood concentrations prior to the next application of the composition, which usually occurs many hours later, or once-a-day. Such a sudden rise of drug concentration in the blood could be dangerous for the patient as it may exceed the drug dose tolerated by the organism. In addition, as the whole dose of active agent is delivered to the bloodstream and tissues in the first hours following the application, the drug's intended effects may not endure until the next application.
There remains a need, therefore, for transdermal pharmaceutical compositions capable of delivering at least a part of their active content in a controlled-release manner, for example through temporary storage in the dermis.